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Open Access Research article

Transcriptome and proteome analysis of tyrosine kinase inhibitor treated canine mast cell tumour cells identifies potentially kit signaling-dependent genes

Robert Klopfleisch1*, Anja Meyer1, Patricia Schlieben1, Angelika Bondzio2, Chris Weise3, Dido Lenze4, Michael Hummel4, Ralf Einspanier2 and Achim D Gruber1

Author Affiliations

1 Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Strasse 15, Berlin, 14163, Germany

2 Department of Veterinary Biochemistry, Berlin, Germany

3 Institute of Chemistry/Biochemistry, Berlin, Germany

4 Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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BMC Veterinary Research 2012, 8:96  doi:10.1186/1746-6148-8-96

Published: 29 June 2012

Abstract

Background

Canine mast cell tumour proliferation depends to a large extent on the activity of KIT, a tyrosine kinase receptor. Inhibitors of the KIT tyrosine kinase have recently been introduced and successfully applied as a therapeutic agent for this tumour type. However, little is known on the downstream target genes of this signaling pathway and molecular changes after inhibition.

Results

Transcriptome analysis of the canine mast cell tumour cell line C2 treated for up to 72 hours with the tyrosine kinase inhibitor masitinib identified significant changes in the expression levels of approximately 3500 genes or 16% of the canine genome. Approximately 40% of these genes had increased mRNA expression levels including genes associated with the pro-proliferative pathways of B- and T-cell receptors, chemokine receptors, steroid hormone receptors and EPO-, RAS and MAP kinase signaling. Proteome analysis of C2 cells treated for 72 hours identified 24 proteins with changed expression levels, most of which being involved in gene transcription, e.g. EIA3, EIA4, TARDBP, protein folding, e.g. HSP90, UCHL3, PDIA3 and protection from oxidative stress, GSTT3, SELENBP1.

Conclusions

Transcriptome and proteome analysis of neoplastic canine mast cells treated with masitinib confirmed the strong important and complex role of KIT in these cells. Approximately 16% of the total canine genome and thus the majority of the active genes were significantly transcriptionally regulated. Most of these changes were associated with reduced proliferation and metabolism of treated cells. Interestingly, several pro-proliferative pathways were up-regulated, which may represent attempts of masitinib treated cells to activate alternative pro-proliferative pathways. These pathways may contain hypothetical targets for a combination therapy with masitinib to further improve its therapeutic effect.

Keywords:
KIT; Mast cell tumour; Dog; 2D-DIGE; MALDI; Mastocytosis; Tyrosine kinase inhibition